By means of ligand-specific nuclear receptors, low-molecular-weight lipid-soluble ligands (e.g., steroid, thyroid hormone, and retinoid) are responsible for regulation of various physiological functions, including ontogenetic morphogenesis, cell proliferation and differentiation, and maintenance of biological homeostasis. In 1990, PPAR, which is a type of nuclear receptor, was identified as a protein which mediates the effect of increasing peroxisome, which is an intracellular organelle responsible for lipolysis. The protein PPARα (peroxisome proliferator activated receptor α) refers to a protein which is activated by a peroxisome proliferator. After identification of PPARα, PPARδ and PPARγ were identified as isoform genes having a structure similar to that of PPARα. Thus, PPAR is known to have three subtypes.
Each PPAR subtype is activated in a ligand-dependent manner, and controls expression of a gene having in a promoter region thereof a PPAR responsive element (PPRE) by forming a heterodimer with RXR (retinoid X receptor) whose ligand is 9-cis-retinoic acid (Non-Patent Documents 1 and 2).
For example, as has been reported, a reporter assay employing the PPRE of ACO (acyl-CoA oxidase), which is known as a key enzyme for fatty acid β-oxidation, has shown that linoleic acid, which is known as a PPAR ligand, enhances ACO transcriptional activity by the mediation of PPARα, PPARδ, or PPARγ (Non-Patent Document 3).
As described hereinbelow, in recent years, PPAR has been elucidated to be involved in many physiological and pathological phenomena.
Specifically, the function of PPARα is considered to be widely involved in biological energy metabolism or homeostasis, such as synthesis, transportation, or secretion of fatty acids, or ATP production in a fat-consuming organ. Particularly, it has been elucidated that expression of the gene of a β-oxidation-related enzyme important for fatty acid metabolism (e.g., ACO, HMG-CoA synthase, acyl-CoA synthase, medium chain acyl-CoA dehydrogenase, fatty acid binding protein, or lipoprotein lipase) is strongly dependent on activation of PPARα. PPARα is highly expressed in the liver, heart, kidney, etc., and a PPARα activator is widely recognized as being effective for activation of lipid metabolism in such an organ.
Activation of fatty acid metabolism in association with activation of PPARα is thought to lead to decomposition of liver fat, amelioration of fatty liver, promotion of decomposition or burning of body fat (e.g., visceral fat or subcutaneous fat), and suppression of obesity. A fibrate drug, which is known as a PPARα activator, has been shown to exhibit the effect of promoting fatty acid burning and the effect of increasing HDL cholesterol level, and has recently been elucidated to exhibit, for example, the effect of increasing expression of an adiponectin receptor. Thus, a fibrate drug has been widely used as a therapeutic drug for hyperglycemia with non-insulin-dependent diabetes, dyslipidemia, hyperglycemia, atherosclerosis, etc. (Non-Patent Document 4 and Patent Documents 1 and 2). Meanwhile, PPARα activators have been reported to be effective for cardiac hypertrophy and ischemic heat disease (Non-Patent Documents 5 and 6).
Therefore, PPARα activators are considered to be widely effective for activation of fatty acid metabolism, promotion of body fat burning, prevention and/or amelioration of obesity, prevention and/or amelioration of dyslipidemia, prevention and/or amelioration of fatty liver, prevention and/or amelioration of insulin resistance increase or diabetes, prevention and/or amelioration of arteriosclerosis, prevention and/or amelioration of cardiac hypertrophy or ischemic heat disease, etc. Also, in recent years, search and development have been actively performed on PPARα activators (Patent Documents 3 to 5).
PPARδ (also called PPARβ, NUC1, or FAAR) was cloned in 1992, and, since then, the function thereof has been unknown for a long period of time. However, in recent years, PPARδ has been elucidated to have various physiological functions through, for example, studies employing genetically modified animals and development of PPARδ-selective agonists. Studies employing mice in which PPARδ is overexpressed have shown that PPARδ suppresses an increase in body weight caused by high-fat diet load, reduces fat weight, reduces blood triglyceride level, or suppresses fatty liver (Non-Patent Document 7). In an experiment in which GW501516 (i.e., a PPARδ-selective agonist) was administered to obese rhesus monkeys, HDL cholesterol level was increased, and triglyceride level and LDL cholesterol level were reduced (Non-Patent Document 8).
Studies on the effect of GW501516-acted skeletal-muscle-derived cells on gene expression have shown that GW501516 induces fatty acid uptake or transportation, or expression of fatty acid metabolism-related genes of mitochondrial β-oxidation enzymes, uncoupling proteins, etc. Also, studies have shown that, in GW501516-administered mice, an increase in body weight caused by high-fat diet load is suppressed, fat weight is reduced, and insulin resistance is ameliorated, as in the case of mice in which adipose tissue-specific PPARδ is overexpressed. In the skeletal muscle of the GW501516-administered mice, induction of fatty acid metabolism-related genes and fatty acid β-oxidation was determined. Therefore, conceivably, activation of PPARδ increases energy consumption in skeletal muscle, which results in suppression of fat accumulation in peripheral tissues, whereby insulin resistance is ameliorated (Non-Patent Document 9). Also, since administration of GW501516 to genetically obese mice suppresses pancreatic islet hypertrophy, GW501516 is considered to have a pancreatic islet protection effect (Non-Patent Document 9).
As has been reported, overexpression of PPARδ in mice in a skeletal muscle-specific manner suppresses obesity or insulin resistance increase. As has also been shown, surprisingly, the amount of so-called “slow-twitch muscle” (or “red muscle”) (i.e., high-endurance muscle fiber containing much mitochondria) is considerably increased in the skeletal muscle of the mice, and thus the mice have excellent physical endurance; i.e., the mice can run for a distance about twice that in the case of control mice (Non-Patent Document 10). Therefore, conceivably, activation of PPARδ is effective for improvement of exercise endurance.
According to a recent report, PPARδ controls insulin sensitivity in the liver. In a suggested mechanism for this control, activation of PPARδ reduces supply of glucose from the liver via activation of a hepatic glycolytic pathway and a pentose phosphate cycle, thereby enhancing insulin sensitivity (Non-Patent Document 11).
As described above, activation of PPARδ leads to an increase in HDL cholesterol level, a reduction in LDL cholesterol level, suppression of obesity, amelioration of insulin resistance/enhancement of insulin sensitivity, activation of fatty acid metabolism, promotion of body fat burning, a reduction in blood triglyceride level, suppression of fatty liver, improvement of physical endurance, etc. Therefore, a PPARδ activator is considered to be effective as a preventive and/or ameliorating agent for arteriosclerosis, a preventive and/or ameliorating agent for obesity, an agent for prevention and/or amelioration of insulin resistance increase, an agent for activation of fatty acid oxidation, an agent for promotion of body fat burning, a preventive and/or ameliorating agent for dyslipidemia, a preventive and/or ameliorating agent for fatty liver, or a physical-endurance-improving agent.
In view of the foregoing, search and development, have been actively performed on PPARδ activators, and flavone compounds, phenoxyacetic acid derivatives, etc have been reported so far (Patent Documents 6 and 7).
PPARγ is a molecule which acts on energy storage in a nutrient-rich state, and serves as a so-called thrifty gene. Particularly, PPARγ2 is expressed with relatively high specificity to adipocytes, and PPARγ2 has been elucidated to play a central role in adipocyte differentiation. As has been shown, a thiazolidine derivative, which is known as a PPARγ ligand, strongly induces adipocyte differentiation, to thereby reduce adipocyte size and to enhance insulin sensitivity. Therefore, a thiazolidine derivative has been widely used as an ameliorating agent for insulin resistance or a therapeutic drug for diabetes. However, problems may arise in that administration of a thiazolidine derivative increases body weight or fat weight, and induces obesity (Non-Patent Document 12).
Thus, conceivably, PPAR activators are widely effective for activation of fatty acid metabolism, promotion of body fat burning, prevention and/or amelioration of obesity, prevention and/or amelioration of dyslipidemia, prevention and/or amelioration of fatty liver, improvement of physical endurance, prevention and/or amelioration of insulin resistance increase or diabetes, prevention and/or amelioration of arteriosclerosis, prevention and/or amelioration of cardiac hypertrophy or ischemic heat disease, etc., and are also effective for prevention and/or amelioration of so-called lifestyle-related diseases or metabolic syndrome.
Tempeh is an Indonesian, traditional, fermented soybean food, and this nutrient-rich food contains proteins, dietary fiber, amino acids, vitamins (vitamin E and vitamin B complex), minerals (e.g., iron), isoflavones, etc. (Patent Document 8). The fermented food tempeh is produced by fermenting soybeans with the tempeh fungus. In view of the efficacy of the components contained in tempeh, tempeh has been suggested to exhibit the effect of suppressing an, increase in cholesterol level, the effect of preventing liver fat accumulation, anti-obesity effect, hemolysis preventing effect, and intestinal regulation effect (Patent Document 8). As has been reported, tempeh contains, at a high concentration, γ-aminobutyric acid, which is known to have the effect of suppressing an increase in blood pressure, the effect of reducing neutral lipid, anti-obesity effect, tranquilizing effect, the effect of ameliorating menopausal symptoms, sleep-promoting effect, alcohol/aldehyde-metabolizing effect, and deodorizing effect (Patent Document 9).
However, it has not been known that an organic solvent extract of a soybean product fermented with the tempeh fungus (hereinafter may be referred to as a “tempeh-fungus-fermented soybean product”) is responsible for PRAR activation, and is effective for, for example, activation of fatty acid metabolism or promotion of body fat burning.